One of the characteristic neurochemical changes in the brains of patients with Alzheimer's disease (AD) is a regional loss in the activity of enzyme markers of the cholinergic system (Perry E. K., "The cholinergic hypothesis--ten years on," Brit. Med. Bull. 1986; 42:63-69). One of these marker enzymes, acetylcholinesterase (AChE, E.C. 3.1.1.7), is, however, present in many of the non-cholinergic neurons in the cortex (Nakamura, S. et al, "Acetylcholinesterase and somatostatin-immunoreactivity coexist in human neocortex," Neurosci. Lett. 1985; 61:183-187; Mesulam, M. M. et al, "Acetylcholinesterase-rich pyramidal neurons in the human neocortex and hippocampus: absence at birth, development during the life span, and dissolution in Alzheimer's disease," Ann. Neurol. 1988; 24:765-773) and in subcortical nuclei (Smith and Cuello, "Alzheimer's disease and acetylcholinesterase-containing neurons," Lancet 1984; ii:513) that also show pathological changes in AD. Accordingly, it has been suggested that AD may be related to an abnormality in neurons that contain a particular molecular form of AChE, which could account for why many different transmitter systems are affected in the disease (Smith and Cuello, supra).
Certain molecular forms of AChE are secreted from nervous tissue into the cerebrospinal fluid (CSF) (Chubb, I. W. et al "Is acetylcholinesterase secreted from central neurons into cerebrospinal fluid?" Neuroscience 1976; 1:57-62; Greenfield and Smith, "The influence of electrical stimulation of certain brain areas on the concentration of acetylcholinesterase in rabbit cerebrospinal fluid," Brain Res. 1979, 177:445-459; and one of the brain regions most affected in AD, the hippocampus, has been shown to be a source of neurosecretory AChE (Appleyard & Smith, "Spontaneous and carbachol-evoked in vivo secretion of acetylcholinesterase from the hippocampus of the rat," Neurochem. Int. 11, 397-406). If the level of AChE in CSF reflects the levels of neuronal AChE in the brain, the widespread decrease in brain AChE levels in patients with AD might lead to lower than normal levels of AChE in the CSF. Since early reports (Johnson and Domino, "Cholinergic enzyme activity of cerebrospinal fluid of patients with various neurological disorders," Clin. Chem. Acta 1971, 35:421-428; Davies, P., "Neurotransmitter-related enzymes in senile dementia of the Alzheimer type," Brain Res. 1979, 171:319-327; Soininen et al, "Acetylcholinesterase activities in cerebrospinal fluid of patients with senile dementia of Alzheimer type," Acta neurol. scand. 1981, 64:217-224), there have been more than 20 accounts in the literature about cholinesterase activity in the CSF of patients with dementia, some of which have described lower levels than in non-demented patients, others of which have described no change in dementia. In the great majority of these reports, the diagnosis of AD was made only by clinical criteria. It is noteworthy that in those studies where histological criteria were used a significantly lower AChE level in ventricular CSF (Appleyard et al, "Decreased CSF acetylcholinesterase activity in Alzheimer's disease," Lancet 1983, ii:452; Appleyard et al, "Cholinesterase activities in cerebrospinal fluid of patients with senile dementia of the Alzheimer type," Brain 1987, 110:1309-1322) and in lumbar CSF (Arendt et al, "Decreased ratio of CSF acetylcholinesterase to butyrylcholinesterase activity in Alzheimer's disease," Lancet 1984, i:173) was found in patients with AD compared to controls. However, another study showed that the levels of AChE in the lumbar CSF of patients with histologically diagnosed AD overlapped with the levels in control patients and it was concluded that such measurements have no diagnostic value (Appleyard et al, 1987, supra).